These continuation studies focus on a large pancreas transplant (PT) population of insulin dependent diabetic (IDDM) patients (pts) in order to better understand diabetic nephropathy (DN), the leading cause of renal failure. Objectives are: (a) to determine whether PT can arrest or reverse the early or the more established lesions of DN, (b) describe the nature of and the message (MRNA) for the extracellular matrix (ECM) molecules which accumulate to produce DN, (c) to evaluate renal structural risk factors for DN, and (d) to describe the structural and functional nephrotoxicity of immunosuppression drugs [Cyclosporin (CSA) and Tacrolimus (FK506)] used in PT. Pts include those with long IDDM duration and established DN lesions undergoing PT alone (PTA), and for the study of early DN lesions, IDDM pts with PT performed a few years after kidney transplant (PAK). We will evaluate the effects of PT on the early and late DN lesions by comparing baseline with 5, 10, and 15 year postPT renal biopsies (bx). Controls will include IDDM pts not undergoing PT with bx at parallel times of native or transplanted kidneys. We will also determine from these controls if DN lesions develop at linear rates and where different lesions develop at different rates. We will study whether glomerular number (GN) is a risk factor for DN in native kidneys by estimating GN from prePT renal bx and ultrasound studies. ECM dynamics will be studied by immunofluorescence microscopy and quantitative immunogold EM immunochemistry and by in situ hybridization. We will evaluate the relationship of dose, blood levels, and duration of CSA and FK506 therapy to nephrotoxicity by morphometric measure of interstitial and glomerular scarring in PTA recipients.